8I2N

The RIPK1 kinase domain in complex with QY7-2B compound

Summary for 8I2N

• Entry DOI: 10.2210/pdb8i2n/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 1, ~{N}-methyl-1-[4-[[[1-methyl-5-(phenylmethyl)pyrazol-3-yl]carbonylamino]methyl]phenyl]benzimidazole-5-carboxamide (3 entities in total)
• Functional Keywords: ripk1, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67894.55

Authors

Gong, X.Y.,Li, Y.,Meng, H.Y.,Pan, L.F. (deposition date: 2023-01-14, release date: 2024-01-31, Last modification date: 2024-08-21)

Primary citation

Qin, Y.,Li, D.,Qi, C.,Xiang, H.,Meng, H.,Liu, J.,Zhou, S.,Gong, X.,Li, Y.,Xu, G.,Zu, R.,Xie, H.,Xu, Y.,Xu, G.,Zhang, Z.,Chen, S.,Pan, L.,Li, Y.,Tan, L.
Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.
Acta Pharm Sin B, 14:319-334, 2024

PubMed Abstract: Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, , which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

PubMed: 38261830
DOI: 10.1016/j.apsb.2023.10.021

Experimental method

X-RAY DIFFRACTION (2.29 Å)